Combinations of RAF Inhibitors and MEK Inhibitors:
Omega-carboxyaryl diphenyl urea compounds, e.g. from published PCT applications WO 00/42012 A1, are known as inhibitors of the enzyme raf kinase. Since the enzyme is a down stream effector of p21ras, the inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, e.g. in the treatment of tumours and/or cancerous cell growth mediated by raf kinase.
From published PCT application WO 2005/009961 A2 it is known that the omega-carboxyaryl diphenyl urea compound cited therein of formula (I) is a potent inhibitor of raf kinase, VEGFR kinase, p38 kinase and PDGFR kinase, which are all molecular targets of interest for the treatment and prevention of osteoporosis, inflammatory disorders, hyper-proliferative disorders, and angiogenesis disorders, including cancer.
Unexpectedly, and this represents a basis of the present invention, when combinations of:                component A: an omega-carboxyaryl-substituted diphenyl urea compound of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein; with        component B: which is an N-(2-arylamino)aryl sulfonamide compound of general formula (II), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein;were evaluated for the treatment of hepatocyte carcinoma, synergistically increased anti-tumor activities were demonstrated with these combinations compared to each monotherapy, providing a fundamental rationale for the clinical combination therapy using:        a compound which inhibits a kinase as mentioned supra, in particular a raf kinase, and        a MEK inhibitor.        
To the Applicant's knowledge, no generic or specific disclosure or suggestion in the prior art is known that either combinations of:
component A: one or more omega-carboxyaryl-substituted diphenyl urea compounds of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein; with
component B: one or more N-(2-arylamino)aryl sulfonamide compounds of general formula (II), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein; and, optionally,
component C: one or more further pharmaceutical agents, as described and defined herein;
in which optionally either or both of said components A and B of any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially, would be effective in the treatment or prophylaxis of a cancer, particularly HCC, and may be effective in the treatment or prophylaxis of a cancer such as NSCLC, CRC, melanoma, pancreatic cancer or breast cancer.
Based on the action of the testing compounds described in this invention, the combinations of the present invention as described and defined herein, show a beneficial effect in the treatment of cancer, particularly HCC, and may be effective in the treatment or prophylaxis of a cancer such as NSCLC, CRC, melanoma, pancreatic cancer or breast cancer.
Accordingly, in accordance with a first aspect, the present invention relates: to combinations of:
component A: one or more omega-carboxyaryl-substituted diphenyl urea compounds of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein; with
component B: one or more N-(2-arylamino)aryl sulfonamide compounds of general formula (II), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein; and, optionally,
component C: one or more further pharmaceutical agents, as described and defined herein;
in which optionally either or both of said components A and B of any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
In accordance with a second aspect, of the present invention relates to the use of any of such combinations as described supra for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly HCC, and may be effective in the treatment or prophylaxis of a cancer such as NSCLC, CRC, melanoma, pancreatic cancer or breast cancer.
Further, in accordance with a third aspect, the present invention relates to a kit comprising:
a combination of:
component A: one or more omega-carboxyaryl-substituted diphenyl urea compounds of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein;
component B: one or more N-(2-arylamino)aryl sulfonamide compounds of general formula (II), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein; and, optionally,
component C: one or more further pharmaceutical agents, as described and defined herein;
in which optionally either or both of components A and B in any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.